The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1), offers the greatest hope for halting the rapid worldwide spread of the Acquired Immune Deficiency Syndrome (AIDS). However, there is concern that antibodies that enhance infection and disease could be induced by some types of HIV vaccines. Such antibodies have been shown to facilitate virus infection in target cells in vitro. Although immune mediated enhancement has been observed in diseases such as dengue and feline infectious peritonitis, its in vivo significance in HIV infection or the simian immunodeficiency virus infection (SIV), is not known. We have designed systematic studies in the areas of HIV infection and HIV and SIV vaccination to determine the significance of ADE in HIV/SIV infection and disease. First, we will determine if the presence of enhancing antibody in sera might be related to disease progression. We will use an infectivity (enhancement) assay to examine ADE in the sera of HIV-1 infected individuals enrolled in the Multicenter AIDS Cohort Study who progress to AIDS at different rates and correlate our in vitro data with clinical data. Second, we will determine if enhancing antibody is related to the type of HIV-1 vaccine by testing the sera of initially seronegative individuals immunized with five different HIV sub-unit vaccines for ADE. Since SIVmac has a similar mechanism of infection, and causes an AIDS-like disease like HIV, it serves as a useful model for vaccine studies and one that can be used to test the efficacy of vaccines, since animals can be challenged with live virus after vaccination. Third, therefore, we will examine plasma from 2 groups of rhesus macaques that have been immunized with subunit vaccines from either SlVmac25l, or a macrophage-tropic strain of SIV, and determine the relationships between enhancing antibody, type of vaccine and susceptibility to infection and disease. Fourth, we will use an enhancing plasma obtained from a macaque that developed a macrophage-tropic strain of SIV to investigate the molecular mechanism by which antibodies can facilitate entry and replication of virus in primary macrophages. We will limit our study to FcR-mediated ADE in macrophages because this is the method observed in diseases for which ADE has been documented to occur and because studies of complement receptor mediated ADE of both HIV and SIV infection have not been found to correlate with disease pathogenesis. These studies will be critical in answering the question of the significance of ADE, in providing information that will help to guarantee the safety of products now in human vaccine trials, and in guiding the design of effective vaccine strategies.